17:I[462708,["/_next/static/chunks/3yo3kiro3bmlp.js","/_next/static/chunks/3vr2wvd8f2efb.js","/_next/static/chunks/2vtmb68_vu-9t.js","/_next/static/chunks/2s8mt6_8wrpfo.js","/_next/static/chunks/3vkulz2i3l61y.js","/_next/static/chunks/1cqw2i1silz0i.js","/_next/static/chunks/14dbm3lm_t629.js","/_next/static/chunks/335_v2mb569ld.js","/_next/static/chunks/3ykn5ops9bft5.js","/_next/static/chunks/3cmavum774kjt.js","/_next/static/chunks/3th-0-a2xf9qs.js","/_next/static/chunks/0p0xpwde6kzmv.js","/_next/static/chunks/401-sxxnzbtf_.js","/_next/static/chunks/0wywtv698a1v0.js","/_next/static/chunks/2botzqwpnrzyj.js"],"ArticleReader"] 18:T4e15,## Summary Vitamin B12 deficiency is a treatable cause of megaloblastic hematopoiesis, neuropathy, myelopathy, cognitive and psychiatric symptoms, glossitis, and multisystem dysfunction. Neurologic injury can occur with a normal hemoglobin and normal mean corpuscular volume; absence of anemia or macrocytosis does not exclude clinically important deficiency.[1] For most adults, initial testing is serum total B12 or active B12 (holotranscobalamin). NICE 2024 uses total B12 <180 ng/L (<133 pmol/L) or active B12 <25 pmol/L as values supporting confirmed deficiency; total B12 180–350 ng/L (133–258 pmol/L) or active B12 25–70 pmol/L is indeterminate. Local validated assay ranges take precedence when materially different.[1] Serum methylmalonic acid (MMA) is the preferred functional follow-up test when B12 is indeterminate, but renal impairment can elevate MMA independently of B12 status. Homocysteine is less specific because folate deficiency, kidney disease, hypothyroidism, and other conditions can raise it.[1] Do not delay replacement when a patient has neurologic deterioration, suspected subacute combined degeneration, severe megaloblastic disease, or another condition likely to worsen while confirmatory testing is pending. Draw pretreatment blood samples first when this can be done without meaningful delay.[1] Major causes include autoimmune gastritis with impaired intrinsic-factor function, total or partial gastrectomy, bariatric surgery, terminal-ileal disease or resection, celiac disease, inadequate intake, medicine-associated deficiency, and nitrous oxide exposure. Anti-intrinsic-factor antibody testing is useful when autoimmune gastritis is suspected, but a negative result does not exclude the diagnosis.[1] Treatment depends on cause, severity, absorption, adherence, and neurologic involvement. NICE recommends lifelong intramuscular replacement for deficiency caused or probably caused by autoimmune gastritis and after total gastrectomy or complete terminal-ileal resection.[1] When oral therapy is selected for malabsorption, use at least 1 mg/day.[1] UK practice commonly uses hydroxocobalamin 1 mg IM three times weekly for 2 weeks when there is no neurologic involvement, followed by maintenance every 2–3 months when continued parenteral therapy is required; neurologic disease uses a more intensive loading strategy linked to clinical improvement rather than a fixed clock-only stop.[2] > **Caution:** Folate can improve the anemia of B12 deficiency while neurologic injury continues. When both deficiencies are possible, obtain diagnostic samples promptly and begin B12 before or with folate replacement. ## Clinical manifestations ### Hematologic - Macrocytosis with or without anemia. - Megaloblastic anemia with macro-ovalocytes and hypersegmented neutrophils. - Leukopenia, thrombocytopenia, or pancytopenia in advanced disease. - Ineffective erythropoiesis with high LDH, indirect hyperbilirubinemia, and low haptoglobin, sometimes mimicking hemolysis. - Inappropriately low reticulocyte production before treatment. Iron deficiency may coexist and can blunt macrocytosis. A normal MCV should therefore not reassure the clinician when neurologic or other compatible features are present. ### Neurologic - Distal paresthesia or numbness. - Loss of vibration and joint-position sense. - Sensory ataxia or gait instability. - Weakness, hyperreflexia, or spasticity. - Subacute combined degeneration involving posterior and lateral spinal columns. - Peripheral neuropathy. - Rare optic neuropathy or autonomic dysfunction. Neurologic injury may become only partly reversible if treatment is delayed. ### Neuropsychiatric - Cognitive change. - Depression or anxiety symptoms. - Irritability. - Psychosis or other major behavioral change in severe cases.[1] ### Mucosal and systemic - Glossitis or oral soreness. - Angular cheilitis. - Fatigue and reduced exercise tolerance. - Dyspnea, palpitations, or presyncope when anemia is substantial. - Weight loss or GI symptoms when the underlying cause is malabsorption or gastric disease. > **Clinical pearl:** Neurologic symptoms with normal hemoglobin, normal MCV, or a B12 value near the lower end of the laboratory range still warrant careful assessment when risk factors are present.[1] ## Causes and risk factors | Mechanism | Common settings | Clinical implication | |---|---|---| | Autoimmune impairment of intrinsic-factor function | Autoimmune gastritis; associated autoimmune thyroid or other autoimmune disease | Test anti-intrinsic-factor antibody; negative testing does not fully exclude autoimmune gastritis.[1] | | Loss of gastric anatomy | Total/partial gastrectomy, bariatric surgery | Total gastrectomy produces an irreversible high-risk state and requires lifelong replacement in the NICE pathway.[1] | | Loss of terminal-ileal absorption | Complete or partial ileal resection, Crohn disease | Complete terminal-ileal resection requires lifelong replacement in the NICE pathway.[1] | | Other malabsorption | Celiac disease, selected pancreatic or small-bowel disorders | Treat underlying disease and replace B12; route depends on severity and absorption. | | Inadequate intake | Diet containing little B12 and few fortified foods, severe dietary restriction, food insecurity | Oral replacement is often effective if absorption is intact. | | Medicine associated | Metformin, prolonged acid suppression, selected other agents | Reassess ongoing need and treat deficiency while exposure persists when necessary. | | Functional inactivation | Nitrous oxide exposure | Serum B12 can be misleading; functional markers are particularly important.[1] | Ask specifically about supplements because nonprescription B12 may raise serum concentrations before tissue deficiency is fully corrected.[1] ## Pathophysiology Vitamin B12 is required for methionine synthase and methylmalonyl-CoA mutase reactions. Deficiency disrupts DNA synthesis in rapidly dividing cells, producing nuclear-cytoplasmic asynchrony and megaloblastic hematopoiesis. Impaired methylation and abnormal fatty-acid metabolism contribute to myelin injury and neurologic disease. Normal absorption requires: 1. liberation of B12 from food in the stomach; 2. binding to intrinsic factor produced by gastric parietal cells; 3. delivery to the terminal ileum; 4. receptor-mediated ileal uptake; 5. transport in blood bound largely to transcobalamin and haptocorrin. Loss of intrinsic factor, gastric anatomy, or terminal-ileal surface therefore produces predictable deficiency phenotypes. Nitrous oxide oxidizes cobalamin and can cause functional deficiency even when total serum B12 is not strikingly low. ## Diagnostic approach ### When to test Test when compatible symptoms or laboratory abnormalities occur, especially in patients with risk factors. Common triggers include: - unexplained macrocytosis; - anemia or pancytopenia; - peripheral neuropathy or sensory ataxia; - cognitive or psychiatric change with relevant risk factors; - glossitis; - previous gastric or ileal surgery; - malabsorptive disease; - prolonged metformin or acid-suppressive therapy when compatible symptoms or blood-count changes occur; - strict dietary avoidance of B12-containing foods; - nitrous oxide exposure.[1] ### Initial laboratory tests Obtain: - CBC with indices; - reticulocyte count when anemia or cytopenia is present; - total B12 or active B12; - blood film when macrocytosis or cytopenia is present; - folate; - ferritin and iron studies when anemia is present or mixed deficiency is plausible; - kidney function for interpretation of MMA and broader differential assessment; - liver and thyroid testing when macrocytosis remains unexplained. ### Interpreting B12 concentrations | Test | Result | Interpretation under NICE 2024 | |---|---:|---| | Total B12 | <180 ng/L (<133 pmol/L) | Confirmed deficiency in the NICE framework.[1] | | Total B12 | 180–350 ng/L (133–258 pmol/L) | Indeterminate; use clinical context and usually MMA.[1] | | Total B12 | >350 ng/L (>258 pmol/L) | Deficiency less likely; investigate alternatives if symptoms persist.[1] | | Active B12 | <25 pmol/L | Confirmed deficiency in the NICE framework.[1] | | Active B12 | 25–70 pmol/L | Indeterminate; consider MMA or homocysteine.[1] | | Active B12 | >70 pmol/L | Deficiency less likely.[1] | Assay-specific local thresholds should be used when validated values differ materially.[1] ### MMA and homocysteine **MMA** rises when intracellular B12-dependent metabolism is impaired. It is especially useful when serum B12 is indeterminate. Reduced kidney function lowers specificity because MMA may rise from impaired clearance.[1] **Homocysteine** can support functional deficiency but is less specific because it rises in folate deficiency, kidney disease, hypothyroidism, and other states.[1] When nitrous oxide exposure is suspected, NICE recommends MMA or homocysteine as the initial biochemical test because total B12 can be falsely reassuring.[1] ### Establishing the cause When autoimmune gastritis is suspected, test **anti-intrinsic-factor antibodies**.[1] A positive result strongly supports the diagnosis. A negative result does not rule it out. Persisting suspicion may justify additional testing or gastroenterology review, including selected use of parietal-cell antibodies, fasting gastrin, or endoscopy depending on the clinical context and local pathway.[1] If no cause is found, NICE recommends celiac serology as part of further evaluation.[1] Review: - gastric and bariatric procedures; - terminal-ileal surgery; - Crohn disease or celiac disease; - diet and fortified food intake; - metformin and acid-suppressive therapy; - nitrous oxide exposure; - associated autoimmune disease. ## Differential diagnosis | Problem | Clues | Next step | |---|---|---| | Folate deficiency | Similar megaloblastosis without classic posterior-column disease | Serum folate and cause assessment | | Copper deficiency | Myelopathy, neuropathy, cytopenia, bariatric surgery, excess zinc | Serum copper, ceruloplasmin, zinc | | Myelodysplastic neoplasm | Persistent macrocytosis/cytopenias despite nutritional correction | Hematology review and marrow testing when indicated | | Alcohol-associated macrocytosis | Exposure history, liver abnormalities | Alcohol and liver assessment | | Hypothyroidism | Cold intolerance, bradycardia, weight gain, other thyroid features | TSH and free thyroxine | | Hemolysis with reticulocytosis | High reticulocytes and hemolytic pattern | Bilirubin, LDH, haptoglobin, DAT when appropriate | | Liver disease | Abnormal liver profile and target cells | Cause-directed liver evaluation | | Structural spinal cord disease | Focal or asymmetric neurologic pattern, pain, sphincter features | Urgent neuroimaging when clinically indicated | ## Management ### When treatment should start immediately Begin replacement without waiting for confirmatory testing when there is strong clinical suspicion plus neurologic deterioration, suspected subacute combined degeneration, severe megaloblastic disease, or another rapidly progressive complication.[1] Obtain pretreatment samples first only when this does not delay care. ### Route selection | Clinical setting | Preferred strategy | Key point | |---|---|---| | Dietary deficiency with intact absorption | Oral B12 is usually appropriate | Continue until diet reliably supplies adequate B12; some patients need longer therapy.[1] | | Malabsorption other than autoimmune gastritis or complete anatomic loss | Oral or IM replacement depending on severity and reliability | If oral therapy is used for malabsorption, prescribe at least 1 mg/day.[1] | | Autoimmune gastritis | Lifelong IM replacement in the NICE pathway | Do not stop because serum B12 normalizes.[1] | | Total gastrectomy | Lifelong IM replacement in the NICE pathway | Irreversible loss of normal absorption.[1] | | Complete terminal-ileal resection | Lifelong IM replacement in the NICE pathway | Irreversible loss of primary absorption site.[1] | | Significant neurologic disease | Prefer prompt parenteral therapy using a jurisdiction-specific loading regimen | Follow neurologic response, not only serum B12. | | Nitrous oxide-associated disease | Stop exposure and replace B12 | Functional markers may be more informative than total B12.[1] | ### Oral therapy When oral treatment is selected in suspected or confirmed malabsorption, NICE recommends **at least 1 mg/day**.[1] The same minimum dose is advised when oral replacement is used in pregnancy or breastfeeding under the NICE pathway.[1] High-dose oral treatment can work because a small fraction of B12 is absorbed passively even without intrinsic factor, but route selection should still account for severity, adherence, neurologic disease, and the irreversibility of the cause.[1,4] ### Intramuscular hydroxocobalamin UK medicines guidance commonly uses: - **without neurologic involvement:** hydroxocobalamin **1 mg IM three times weekly for 2 weeks**; - **maintenance when ongoing parenteral treatment is required:** **1 mg IM every 2–3 months**.[2] When neurologic involvement is present, UK practice uses more frequent initial injections and continues intensive treatment until further clinical improvement is no longer occurring, followed by maintenance according to cause and local protocol.[2] > **Caution:** Do not use a fixed number of days as the sole reason to stop intensive treatment in active neurologic B12 deficiency. Clinical response, diagnosis, cause, and specialist guidance matter. ### Jurisdiction differences Hydroxocobalamin is commonly used in the United Kingdom, whereas cyanocobalamin is widely used in other jurisdictions. Product strengths, loading schedules, and maintenance intervals differ. Follow the licensed local product information and national pathway rather than transferring one country's exact injection schedule to another without verification. ### Correct associated deficiencies Iron and folate deficiency often coexist. Marrow recovery can uncover iron deficiency after B12 treatment begins. Replace iron when indicated. If folate deficiency is also present, start B12 before or at the same time as folate therapy. ## Expected response Clinical and laboratory recovery varies with severity and duration. - Symptoms may begin improving within 2 weeks but may take up to 3 months or longer.[1] - Reticulocytosis generally appears within the first week of effective therapy. - Hemoglobin and cytopenias improve over subsequent weeks. - Neurologic recovery may take months. - Long-standing myelopathy or neuropathy may remain partly irreversible. Failure to improve should prompt review of: - diagnosis; - adherence; - oral dose; - route of replacement; - ongoing nitrous oxide exposure; - malabsorption; - iron, folate, or copper deficiency; - structural or alternative neurologic disease; - marrow disease when cytopenias persist. ## Monitoring ### Oral replacement At follow-up assess: - symptom trajectory; - CBC response when initially abnormal; - adherence and dose; - persistence of the underlying cause. If symptoms persist despite oral therapy, NICE supports reassessment of dose and adherence, consideration of MMA or homocysteine, and switching to intramuscular therapy when needed.[1] ### Intramuscular replacement Do **not** repeat the original serum B12 test simply to monitor a patient receiving regular IM replacement.[1] The concentration reflects administered B12 and does not indicate tissue-level clinical response. Follow: - neurologic symptoms and function; - hematologic response when initially abnormal; - recurrence of symptoms before the next injection; - treatment access and adherence; - cause-specific needs. For irreversible causes, continue lifelong IM replacement even when symptoms have resolved.[1] ## Autoimmune gastritis and gastric neoplasia risk Autoimmune gastritis is associated with increased risk of gastric neuroendocrine tumors and may increase gastric adenocarcinoma risk.[1] At follow-up, new or worsening upper-GI symptoms, unexplained weight loss, recurrent vomiting, dyspepsia, or unexplained iron deficiency should prompt consideration of gastroenterology referral and endoscopy according to local cancer pathways.[1] Routine endoscopic schedules vary by jurisdiction and individual risk; the presence of B12 deficiency alone does not define one universal surveillance interval. ## Special situations ### Pregnancy and breastfeeding Do not withhold necessary treatment. NICE recommends active B12 as the initial diagnostic test during pregnancy and suggests at least **1 mg/day** when oral replacement is used.[1] UK guidance does not require a different hydroxocobalamin dose solely because of pregnancy, but earlier symptom review is advised.[2] ### Chronic kidney disease Reduced kidney function can increase MMA, making the test less specific. Interpret MMA alongside eGFR, symptoms, initial B12 concentration, and treatment response. ### Metformin exposure Metformin can contribute to B12 deficiency. In a person with diabetes and neuropathy, macrocytosis, anemia, or other risk factors, do not assume symptoms are caused only by diabetes. Treat confirmed deficiency while reassessing the ongoing medicine indication; metformin itself does not usually need to be stopped when it remains clinically beneficial. ### Nitrous oxide exposure Ask directly and nonjudgmentally about recreational, occupational, and procedural exposure. Nitrous oxide inactivates cobalamin and may produce severe neurologic disease despite a serum B12 concentration that is not markedly low. Stop exposure, obtain functional testing when feasible, and treat promptly.[1] ## Disposition and referral Most uncomplicated deficiency can be managed in outpatient care. Seek urgent neurologic or hospital assessment for: - progressive weakness or gait failure; - rapidly evolving myelopathy; - sphincter dysfunction; - severe pancytopenia with physiologic compromise; - diagnostic concern for spinal cord compression or another neurologic emergency. Refer to hematology when: - cytopenias do not respond as expected; - marrow disease remains possible; - the diagnosis is uncertain. Refer to gastroenterology when: - malabsorption is unexplained; - autoimmune gastritis is suspected with concerning upper-GI symptoms; - recurrent deficiency persists despite adequate replacement; - celiac or other structural GI disease requires further workup. ## Related library topics - [Iron Deficiency Anemia](iron-deficiency-anemia.md) - [Celiac Disease](../gastroenterology/celiac-disease.md) - [Chronic Pancreatitis](../gastroenterology/chronic-pancreatitis.md) - [Crohn Disease and Ulcerative Colitis](../gastroenterology/inflammatory-bowel-disease-in-adults.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Hypothyroidism in Adults](../endocrinology/hypothyroidism-in-adults.md) ## References 1. National Institute for Health and Care Excellence. **Vitamin B12 deficiency in over 16s: diagnosis and management (NG239).** NICE; 2024. Published 6 March 2024. https://www.nice.org.uk/guidance/ng239 2. NHS Specialist Pharmacy Service. **Vitamin B12 deficiency: treatment during pregnancy.** Updated 2024. https://www.sps.nhs.uk/articles/vitamin-b12-deficiency-treatment-during-pregnancy/ 3. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. **Guidelines for the diagnosis and treatment of cobalamin and folate disorders.** Br J Haematol. 2014;166(4):496-513. doi:10.1111/bjh.12959. PMID:24942828. https://pubmed.ncbi.nlm.nih.gov/24942828/ 4. Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. **Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.** Cochrane Database Syst Rev. 2018;3:CD004655. doi:10.1002/14651858.CD004655.pub3. PMID:29543316. https://pubmed.ncbi.nlm.nih.gov/29543316/19:T4e15,## Summary Vitamin B12 deficiency is a treatable cause of megaloblastic hematopoiesis, neuropathy, myelopathy, cognitive and psychiatric symptoms, glossitis, and multisystem dysfunction. Neurologic injury can occur with a normal hemoglobin and normal mean corpuscular volume; absence of anemia or macrocytosis does not exclude clinically important deficiency.[1] For most adults, initial testing is serum total B12 or active B12 (holotranscobalamin). NICE 2024 uses total B12 <180 ng/L (<133 pmol/L) or active B12 <25 pmol/L as values supporting confirmed deficiency; total B12 180–350 ng/L (133–258 pmol/L) or active B12 25–70 pmol/L is indeterminate. Local validated assay ranges take precedence when materially different.[1] Serum methylmalonic acid (MMA) is the preferred functional follow-up test when B12 is indeterminate, but renal impairment can elevate MMA independently of B12 status. Homocysteine is less specific because folate deficiency, kidney disease, hypothyroidism, and other conditions can raise it.[1] Do not delay replacement when a patient has neurologic deterioration, suspected subacute combined degeneration, severe megaloblastic disease, or another condition likely to worsen while confirmatory testing is pending. Draw pretreatment blood samples first when this can be done without meaningful delay.[1] Major causes include autoimmune gastritis with impaired intrinsic-factor function, total or partial gastrectomy, bariatric surgery, terminal-ileal disease or resection, celiac disease, inadequate intake, medicine-associated deficiency, and nitrous oxide exposure. Anti-intrinsic-factor antibody testing is useful when autoimmune gastritis is suspected, but a negative result does not exclude the diagnosis.[1] Treatment depends on cause, severity, absorption, adherence, and neurologic involvement. NICE recommends lifelong intramuscular replacement for deficiency caused or probably caused by autoimmune gastritis and after total gastrectomy or complete terminal-ileal resection.[1] When oral therapy is selected for malabsorption, use at least 1 mg/day.[1] UK practice commonly uses hydroxocobalamin 1 mg IM three times weekly for 2 weeks when there is no neurologic involvement, followed by maintenance every 2–3 months when continued parenteral therapy is required; neurologic disease uses a more intensive loading strategy linked to clinical improvement rather than a fixed clock-only stop.[2] > **Caution:** Folate can improve the anemia of B12 deficiency while neurologic injury continues. When both deficiencies are possible, obtain diagnostic samples promptly and begin B12 before or with folate replacement. ## Clinical manifestations ### Hematologic - Macrocytosis with or without anemia. - Megaloblastic anemia with macro-ovalocytes and hypersegmented neutrophils. - Leukopenia, thrombocytopenia, or pancytopenia in advanced disease. - Ineffective erythropoiesis with high LDH, indirect hyperbilirubinemia, and low haptoglobin, sometimes mimicking hemolysis. - Inappropriately low reticulocyte production before treatment. Iron deficiency may coexist and can blunt macrocytosis. A normal MCV should therefore not reassure the clinician when neurologic or other compatible features are present. ### Neurologic - Distal paresthesia or numbness. - Loss of vibration and joint-position sense. - Sensory ataxia or gait instability. - Weakness, hyperreflexia, or spasticity. - Subacute combined degeneration involving posterior and lateral spinal columns. - Peripheral neuropathy. - Rare optic neuropathy or autonomic dysfunction. Neurologic injury may become only partly reversible if treatment is delayed. ### Neuropsychiatric - Cognitive change. - Depression or anxiety symptoms. - Irritability. - Psychosis or other major behavioral change in severe cases.[1] ### Mucosal and systemic - Glossitis or oral soreness. - Angular cheilitis. - Fatigue and reduced exercise tolerance. - Dyspnea, palpitations, or presyncope when anemia is substantial. - Weight loss or GI symptoms when the underlying cause is malabsorption or gastric disease. > **Clinical pearl:** Neurologic symptoms with normal hemoglobin, normal MCV, or a B12 value near the lower end of the laboratory range still warrant careful assessment when risk factors are present.[1] ## Causes and risk factors | Mechanism | Common settings | Clinical implication | |---|---|---| | Autoimmune impairment of intrinsic-factor function | Autoimmune gastritis; associated autoimmune thyroid or other autoimmune disease | Test anti-intrinsic-factor antibody; negative testing does not fully exclude autoimmune gastritis.[1] | | Loss of gastric anatomy | Total/partial gastrectomy, bariatric surgery | Total gastrectomy produces an irreversible high-risk state and requires lifelong replacement in the NICE pathway.[1] | | Loss of terminal-ileal absorption | Complete or partial ileal resection, Crohn disease | Complete terminal-ileal resection requires lifelong replacement in the NICE pathway.[1] | | Other malabsorption | Celiac disease, selected pancreatic or small-bowel disorders | Treat underlying disease and replace B12; route depends on severity and absorption. | | Inadequate intake | Diet containing little B12 and few fortified foods, severe dietary restriction, food insecurity | Oral replacement is often effective if absorption is intact. | | Medicine associated | Metformin, prolonged acid suppression, selected other agents | Reassess ongoing need and treat deficiency while exposure persists when necessary. | | Functional inactivation | Nitrous oxide exposure | Serum B12 can be misleading; functional markers are particularly important.[1] | Ask specifically about supplements because nonprescription B12 may raise serum concentrations before tissue deficiency is fully corrected.[1] ## Pathophysiology Vitamin B12 is required for methionine synthase and methylmalonyl-CoA mutase reactions. Deficiency disrupts DNA synthesis in rapidly dividing cells, producing nuclear-cytoplasmic asynchrony and megaloblastic hematopoiesis. Impaired methylation and abnormal fatty-acid metabolism contribute to myelin injury and neurologic disease. Normal absorption requires: 1. liberation of B12 from food in the stomach; 2. binding to intrinsic factor produced by gastric parietal cells; 3. delivery to the terminal ileum; 4. receptor-mediated ileal uptake; 5. transport in blood bound largely to transcobalamin and haptocorrin. Loss of intrinsic factor, gastric anatomy, or terminal-ileal surface therefore produces predictable deficiency phenotypes. Nitrous oxide oxidizes cobalamin and can cause functional deficiency even when total serum B12 is not strikingly low. ## Diagnostic approach ### When to test Test when compatible symptoms or laboratory abnormalities occur, especially in patients with risk factors. Common triggers include: - unexplained macrocytosis; - anemia or pancytopenia; - peripheral neuropathy or sensory ataxia; - cognitive or psychiatric change with relevant risk factors; - glossitis; - previous gastric or ileal surgery; - malabsorptive disease; - prolonged metformin or acid-suppressive therapy when compatible symptoms or blood-count changes occur; - strict dietary avoidance of B12-containing foods; - nitrous oxide exposure.[1] ### Initial laboratory tests Obtain: - CBC with indices; - reticulocyte count when anemia or cytopenia is present; - total B12 or active B12; - blood film when macrocytosis or cytopenia is present; - folate; - ferritin and iron studies when anemia is present or mixed deficiency is plausible; - kidney function for interpretation of MMA and broader differential assessment; - liver and thyroid testing when macrocytosis remains unexplained. ### Interpreting B12 concentrations | Test | Result | Interpretation under NICE 2024 | |---|---:|---| | Total B12 | <180 ng/L (<133 pmol/L) | Confirmed deficiency in the NICE framework.[1] | | Total B12 | 180–350 ng/L (133–258 pmol/L) | Indeterminate; use clinical context and usually MMA.[1] | | Total B12 | >350 ng/L (>258 pmol/L) | Deficiency less likely; investigate alternatives if symptoms persist.[1] | | Active B12 | <25 pmol/L | Confirmed deficiency in the NICE framework.[1] | | Active B12 | 25–70 pmol/L | Indeterminate; consider MMA or homocysteine.[1] | | Active B12 | >70 pmol/L | Deficiency less likely.[1] | Assay-specific local thresholds should be used when validated values differ materially.[1] ### MMA and homocysteine **MMA** rises when intracellular B12-dependent metabolism is impaired. It is especially useful when serum B12 is indeterminate. Reduced kidney function lowers specificity because MMA may rise from impaired clearance.[1] **Homocysteine** can support functional deficiency but is less specific because it rises in folate deficiency, kidney disease, hypothyroidism, and other states.[1] When nitrous oxide exposure is suspected, NICE recommends MMA or homocysteine as the initial biochemical test because total B12 can be falsely reassuring.[1] ### Establishing the cause When autoimmune gastritis is suspected, test **anti-intrinsic-factor antibodies**.[1] A positive result strongly supports the diagnosis. A negative result does not rule it out. Persisting suspicion may justify additional testing or gastroenterology review, including selected use of parietal-cell antibodies, fasting gastrin, or endoscopy depending on the clinical context and local pathway.[1] If no cause is found, NICE recommends celiac serology as part of further evaluation.[1] Review: - gastric and bariatric procedures; - terminal-ileal surgery; - Crohn disease or celiac disease; - diet and fortified food intake; - metformin and acid-suppressive therapy; - nitrous oxide exposure; - associated autoimmune disease. ## Differential diagnosis | Problem | Clues | Next step | |---|---|---| | Folate deficiency | Similar megaloblastosis without classic posterior-column disease | Serum folate and cause assessment | | Copper deficiency | Myelopathy, neuropathy, cytopenia, bariatric surgery, excess zinc | Serum copper, ceruloplasmin, zinc | | Myelodysplastic neoplasm | Persistent macrocytosis/cytopenias despite nutritional correction | Hematology review and marrow testing when indicated | | Alcohol-associated macrocytosis | Exposure history, liver abnormalities | Alcohol and liver assessment | | Hypothyroidism | Cold intolerance, bradycardia, weight gain, other thyroid features | TSH and free thyroxine | | Hemolysis with reticulocytosis | High reticulocytes and hemolytic pattern | Bilirubin, LDH, haptoglobin, DAT when appropriate | | Liver disease | Abnormal liver profile and target cells | Cause-directed liver evaluation | | Structural spinal cord disease | Focal or asymmetric neurologic pattern, pain, sphincter features | Urgent neuroimaging when clinically indicated | ## Management ### When treatment should start immediately Begin replacement without waiting for confirmatory testing when there is strong clinical suspicion plus neurologic deterioration, suspected subacute combined degeneration, severe megaloblastic disease, or another rapidly progressive complication.[1] Obtain pretreatment samples first only when this does not delay care. ### Route selection | Clinical setting | Preferred strategy | Key point | |---|---|---| | Dietary deficiency with intact absorption | Oral B12 is usually appropriate | Continue until diet reliably supplies adequate B12; some patients need longer therapy.[1] | | Malabsorption other than autoimmune gastritis or complete anatomic loss | Oral or IM replacement depending on severity and reliability | If oral therapy is used for malabsorption, prescribe at least 1 mg/day.[1] | | Autoimmune gastritis | Lifelong IM replacement in the NICE pathway | Do not stop because serum B12 normalizes.[1] | | Total gastrectomy | Lifelong IM replacement in the NICE pathway | Irreversible loss of normal absorption.[1] | | Complete terminal-ileal resection | Lifelong IM replacement in the NICE pathway | Irreversible loss of primary absorption site.[1] | | Significant neurologic disease | Prefer prompt parenteral therapy using a jurisdiction-specific loading regimen | Follow neurologic response, not only serum B12. | | Nitrous oxide-associated disease | Stop exposure and replace B12 | Functional markers may be more informative than total B12.[1] | ### Oral therapy When oral treatment is selected in suspected or confirmed malabsorption, NICE recommends **at least 1 mg/day**.[1] The same minimum dose is advised when oral replacement is used in pregnancy or breastfeeding under the NICE pathway.[1] High-dose oral treatment can work because a small fraction of B12 is absorbed passively even without intrinsic factor, but route selection should still account for severity, adherence, neurologic disease, and the irreversibility of the cause.[1,4] ### Intramuscular hydroxocobalamin UK medicines guidance commonly uses: - **without neurologic involvement:** hydroxocobalamin **1 mg IM three times weekly for 2 weeks**; - **maintenance when ongoing parenteral treatment is required:** **1 mg IM every 2–3 months**.[2] When neurologic involvement is present, UK practice uses more frequent initial injections and continues intensive treatment until further clinical improvement is no longer occurring, followed by maintenance according to cause and local protocol.[2] > **Caution:** Do not use a fixed number of days as the sole reason to stop intensive treatment in active neurologic B12 deficiency. Clinical response, diagnosis, cause, and specialist guidance matter. ### Jurisdiction differences Hydroxocobalamin is commonly used in the United Kingdom, whereas cyanocobalamin is widely used in other jurisdictions. Product strengths, loading schedules, and maintenance intervals differ. Follow the licensed local product information and national pathway rather than transferring one country's exact injection schedule to another without verification. ### Correct associated deficiencies Iron and folate deficiency often coexist. Marrow recovery can uncover iron deficiency after B12 treatment begins. Replace iron when indicated. If folate deficiency is also present, start B12 before or at the same time as folate therapy. ## Expected response Clinical and laboratory recovery varies with severity and duration. - Symptoms may begin improving within 2 weeks but may take up to 3 months or longer.[1] - Reticulocytosis generally appears within the first week of effective therapy. - Hemoglobin and cytopenias improve over subsequent weeks. - Neurologic recovery may take months. - Long-standing myelopathy or neuropathy may remain partly irreversible. Failure to improve should prompt review of: - diagnosis; - adherence; - oral dose; - route of replacement; - ongoing nitrous oxide exposure; - malabsorption; - iron, folate, or copper deficiency; - structural or alternative neurologic disease; - marrow disease when cytopenias persist. ## Monitoring ### Oral replacement At follow-up assess: - symptom trajectory; - CBC response when initially abnormal; - adherence and dose; - persistence of the underlying cause. If symptoms persist despite oral therapy, NICE supports reassessment of dose and adherence, consideration of MMA or homocysteine, and switching to intramuscular therapy when needed.[1] ### Intramuscular replacement Do **not** repeat the original serum B12 test simply to monitor a patient receiving regular IM replacement.[1] The concentration reflects administered B12 and does not indicate tissue-level clinical response. Follow: - neurologic symptoms and function; - hematologic response when initially abnormal; - recurrence of symptoms before the next injection; - treatment access and adherence; - cause-specific needs. For irreversible causes, continue lifelong IM replacement even when symptoms have resolved.[1] ## Autoimmune gastritis and gastric neoplasia risk Autoimmune gastritis is associated with increased risk of gastric neuroendocrine tumors and may increase gastric adenocarcinoma risk.[1] At follow-up, new or worsening upper-GI symptoms, unexplained weight loss, recurrent vomiting, dyspepsia, or unexplained iron deficiency should prompt consideration of gastroenterology referral and endoscopy according to local cancer pathways.[1] Routine endoscopic schedules vary by jurisdiction and individual risk; the presence of B12 deficiency alone does not define one universal surveillance interval. ## Special situations ### Pregnancy and breastfeeding Do not withhold necessary treatment. NICE recommends active B12 as the initial diagnostic test during pregnancy and suggests at least **1 mg/day** when oral replacement is used.[1] UK guidance does not require a different hydroxocobalamin dose solely because of pregnancy, but earlier symptom review is advised.[2] ### Chronic kidney disease Reduced kidney function can increase MMA, making the test less specific. Interpret MMA alongside eGFR, symptoms, initial B12 concentration, and treatment response. ### Metformin exposure Metformin can contribute to B12 deficiency. In a person with diabetes and neuropathy, macrocytosis, anemia, or other risk factors, do not assume symptoms are caused only by diabetes. Treat confirmed deficiency while reassessing the ongoing medicine indication; metformin itself does not usually need to be stopped when it remains clinically beneficial. ### Nitrous oxide exposure Ask directly and nonjudgmentally about recreational, occupational, and procedural exposure. Nitrous oxide inactivates cobalamin and may produce severe neurologic disease despite a serum B12 concentration that is not markedly low. Stop exposure, obtain functional testing when feasible, and treat promptly.[1] ## Disposition and referral Most uncomplicated deficiency can be managed in outpatient care. Seek urgent neurologic or hospital assessment for: - progressive weakness or gait failure; - rapidly evolving myelopathy; - sphincter dysfunction; - severe pancytopenia with physiologic compromise; - diagnostic concern for spinal cord compression or another neurologic emergency. Refer to hematology when: - cytopenias do not respond as expected; - marrow disease remains possible; - the diagnosis is uncertain. Refer to gastroenterology when: - malabsorption is unexplained; - autoimmune gastritis is suspected with concerning upper-GI symptoms; - recurrent deficiency persists despite adequate replacement; - celiac or other structural GI disease requires further workup. ## Related library topics - [Iron Deficiency Anemia](iron-deficiency-anemia.md) - [Celiac Disease](../gastroenterology/celiac-disease.md) - [Chronic Pancreatitis](../gastroenterology/chronic-pancreatitis.md) - [Crohn Disease and Ulcerative Colitis](../gastroenterology/inflammatory-bowel-disease-in-adults.md) - [Chronic Kidney Disease](../nephrology/chronic-kidney-disease.md) - [Hypothyroidism in Adults](../endocrinology/hypothyroidism-in-adults.md) ## References 1. National Institute for Health and Care Excellence. **Vitamin B12 deficiency in over 16s: diagnosis and management (NG239).** NICE; 2024. Published 6 March 2024. https://www.nice.org.uk/guidance/ng239 2. NHS Specialist Pharmacy Service. **Vitamin B12 deficiency: treatment during pregnancy.** Updated 2024. https://www.sps.nhs.uk/articles/vitamin-b12-deficiency-treatment-during-pregnancy/ 3. Devalia V, Hamilton MS, Molloy AM; British Committee for Standards in Haematology. **Guidelines for the diagnosis and treatment of cobalamin and folate disorders.** Br J Haematol. 2014;166(4):496-513. doi:10.1111/bjh.12959. PMID:24942828. https://pubmed.ncbi.nlm.nih.gov/24942828/ 4. Wang H, Li L, Qin LL, Song Y, Vidal-Alaball J, Liu TH. **Oral vitamin B12 versus intramuscular vitamin B12 for vitamin B12 deficiency.** Cochrane Database Syst Rev. 2018;3:CD004655. doi:10.1002/14651858.CD004655.pub3. PMID:29543316. https://pubmed.ncbi.nlm.nih.gov/29543316/7:["$","$L17",null,{"article":{"id":"medical-vitamin-b12-deficiency-in-adults","title":"Vitamin B12 Deficiency in Adults","slug":"vitamin-b12-deficiency-in-adults","description":"Vitamin B12 deficiency is a treatable cause of megaloblastic hematopoiesis, neuropathy, myelopathy, cognitive and psychiatric symptoms, glossitis, and multisystem dysfunction. Neurologic injury can occur with a normal…","aliases":[],"category":"Hematology","tags":["Hematology"],"updatedAt":"$undefined","body":"$18","headings":[{"id":"summary","text":"Summary","level":2},{"id":"clinical-manifestations","text":"Clinical manifestations","level":2},{"id":"hematologic","text":"Hematologic","level":3},{"id":"neurologic","text":"Neurologic","level":3},{"id":"neuropsychiatric","text":"Neuropsychiatric","level":3},{"id":"mucosal-and-systemic","text":"Mucosal and systemic","level":3},{"id":"causes-and-risk-factors","text":"Causes and risk factors","level":2},{"id":"pathophysiology","text":"Pathophysiology","level":2},{"id":"diagnostic-approach","text":"Diagnostic approach","level":2},{"id":"when-to-test","text":"When to test","level":3},{"id":"initial-laboratory-tests","text":"Initial laboratory tests","level":3},{"id":"interpreting-b12-concentrations","text":"Interpreting B12 concentrations","level":3},{"id":"mma-and-homocysteine","text":"MMA and homocysteine","level":3},{"id":"establishing-the-cause","text":"Establishing the cause","level":3},{"id":"differential-diagnosis","text":"Differential diagnosis","level":2},{"id":"management","text":"Management","level":2},{"id":"when-treatment-should-start-immediately","text":"When treatment should start immediately","level":3},{"id":"route-selection","text":"Route selection","level":3},{"id":"oral-therapy","text":"Oral therapy","level":3},{"id":"intramuscular-hydroxocobalamin","text":"Intramuscular hydroxocobalamin","level":3},{"id":"jurisdiction-differences","text":"Jurisdiction differences","level":3},{"id":"correct-associated-deficiencies","text":"Correct associated deficiencies","level":3},{"id":"expected-response","text":"Expected response","level":2},{"id":"monitoring","text":"Monitoring","level":2},{"id":"oral-replacement","text":"Oral replacement","level":3},{"id":"intramuscular-replacement","text":"Intramuscular replacement","level":3},{"id":"autoimmune-gastritis-and-gastric-neoplasia-risk","text":"Autoimmune gastritis and gastric neoplasia risk","level":2},{"id":"special-situations","text":"Special situations","level":2},{"id":"pregnancy-and-breastfeeding","text":"Pregnancy and breastfeeding","level":3},{"id":"chronic-kidney-disease","text":"Chronic kidney disease","level":3},{"id":"metformin-exposure","text":"Metformin exposure","level":3},{"id":"nitrous-oxide-exposure","text":"Nitrous oxide exposure","level":3},{"id":"disposition-and-referral","text":"Disposition and referral","level":2},{"id":"related-library-topics","text":"Related library topics","level":2},{"id":"references","text":"References","level":2}],"readingMinutes":12},"linkedMarkdown":"$19","backlinks":[],"related":[],"previewBySlug":{"abcde-approach":{"title":"ABCDE Approach","description":"The ABCDE approach is a structured method for the immediate assessment and treatment of a deteriorating or critically ill patient: Airway, Breathing, Circulation, Disability, Exposure. 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