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vitamin B12 deficiency

Etiology: 1) pernicious anemia (autoimmune atrophic gastritis) {most common cause [5]} 2) food-cobalamin malabsorption - inability to split cobalamin from its binding in food (50% of cases) [6] 3) transcobalamin II deficiency 4) dietary: vegans 5) hypochlorhydria, atrophic gastritis 6) post surgical: gastrectomy or ileal resection 7) pancreatic insufficiency [20] 8) Crohn's disease 9) parasitic or bacterial overgrowth of small intestine a) blind loop syndrome b) Diphyllobothrium latum, Giardia lamblia, Taenia [15] c) high serum folate 10) inherited condition in which a histologically normal stomach secretes either an abnormal intrinsic factor or none at all 11) pharmaceutical agents may contribute a) chronic use of nitrous oxide oxidizes cobalamin b) drugs which interfere with absorption of vit B12 1] neomycin 2] colchicine 3] ethanol (alcohol abuse) [20] 4] metformin (esp without Ca+2 supplementation) [13,18,20] c) chronic gastric acid suppression (> 2 years) [24] 1] proton pump inhibitor use 2] histamine H2 receptor antagonist use 12) Helicobacter pylori infection 13) age > 75 years [32] 14) autoantibody targeting transcobalamin receptor (CD320) in CSF [34] - CNS restricted symptoms Epidemiology: - 3-5% of elderly [3] - in the UK & USA: 6% of adults < 60 years, 20% > 60 years [32] Pathology: 1) subacute combined degeneration of peripheral nerves & spinal cord a) changes begin in the posterior columns &/or lateral columns of the lower cervical & upper thoracic spinal cord b) demyelination & wallerian axonal degeneration c) phagocytosis by macrophages & reactive astrocytosis d) increased tissue levels of methylmalonyl CoA & its precursor propionyl CoA lead to synthesis of non-physiologic fatty acids & their incorporation into neuronal lipids [7] 2) cerebral hemisphere pathology less well defined 3) pernicious anemia (chronic autoimmune atrophic gastritis) 4) megaloblastic anemia - ineffective erythropoiesis may result in hemolytic anemia 5) not associated with vascular brain changes Clinical manifestations: 1) paresthesias early in the course of the illness 2) abnormal sensation of position & vibration - positive Romberg sign 3) muscle weakness - calf muscle atrophy 4) spasticity 5) gait disturbance, ataxia 6) diminished deep tendon reflexes - case of hyperreflexia & positive Babinski reflex [31] 7) decreased pain & temperature sensation 8) psychiatric disturbances a) mood & personality changes b) psychosis c) delirium d) memory impairment (dementia, Wernicke's syndrome [10]) - dementia due to vitamin B12 deficiency is rare [20] 9) signs & symptoms of anemia - neurologic changes may precede anemia [3] 10) jaundice may result from ineffective erythropoiesis 11) 'beefy red' glossitis (macroglossia) 12) orthostatic tremor (may be presenting symptom) 13) seizures (unusual) [11] 14) non-specific GI symptoms, abdominal pain (GRS9) [20] 15) weight loss with more severe vitamin B12 deficiency [20,30] 16) not a cause of changes in bowel or bladder function [20] Laboratory: 1) features of megaloblastic anemia may be observed a) complete blood count (CBC) may show pancytopenia 1] anemia may or may not be present 2] MCV may be elevated or normal 3] RDW may be elevated 4] red cell indexes may be difficult to interpret if also iron-deficiency 5] thrombocytopenia 6] leukopenia b) peripheral blood smear may show macrocytes & hypersegmented neutrophils c) may show evidence of hemolysis [3,22] 2) serum vitamin B12 level a) < 200 pg/mL suggestive of vitamin B12 deficiency b) < 100 pg/mL is diagnostic c) serum levels may be normal with defective conversion of cobalamin to active coenzyme d) preferred initial diagnostic test for vitamin B12 deficiency [3] 3) serum methylmalonic acid is increased - more sensitive & specific than serum vitamin B12 level [3] 4) increased urinary methylmalonic acid 5) serum homocysteine may be elevated [12] 6) Schilling test (gold standard) 7) evidence of pernicious anemia a) serum gastrin levels is often high b) anti-parietal cell antibody is often positive c) intrinsic factor antibody is often positive - testing not indicated for diagnostic purposes [3] c) gastric pH may be high with pernicious anemia 8) deoxyuridine suppression test (dUST) {rarely done} 9) vitamin B12 binding capacity 10) serum holotranscobalamin 2 is diminished [16] - may not be useful in patients with renal insufficiency 11) ineffective erythopoiesis may result in hemolytic anemia a) increased serum unconjugated bilirubin b) increased serum lactate dehydrogenase c) direct antiglobulin test is negative [3,22] 12) cobalamin/propionate/homocysteine metabolism related disorders panel (ARUP) 13) bone marrow biopsy unnecessary [3] Special laboratory: 1) electroencephalography is abnormal (50%) [6] 2) evoked potentials are abnormal (50%) [6] Radiology: - magnetic resonance imaging of the cervical/thoracic spine a) hyperintensity of the posterior columns &/or lateral columns on T2-weighted images [8] b) MRI abnormalities may persist after treatment [8] c) pathology generally involves both posterior columns & lateral columns or cord in general at thoracic level Complications: 1) poor response to pneumovax in elderly patients with vitamin B12 deficiency 2) increased risk of gastric cancer & gastric carcinoid 3) atrophic gastritis, pernicious anemia - small intestinal bacterial overgrowth 4) no association of low plasma vitamin B12 levels & dementia & association (or lack of) unaffected by vitamin B12 supplementation [33] 5) no evidence that vitamin B12 deficiency is associated with vascular pathology even though there is an association between low vitamin B12 & increased homocysteine levels [20] 6) no evidence vitamin B12 deficiency increases risk of Alzheimer's disease [20] Differential diagnosis: - copper deficiency (overlap of clinical manifestations) [20] - coexisting vitamin B12 deficiency & iron deficiency [20] Management: 1) simple vitamin B12 deficiency includng food-cobalmin malabsorption a) oral vitamin B12 (cyanocobalamin) 1000-2000 ug PO QD [3,17] - RDA is 2.4 ug/day b) initial treatment of choice for all vitamin B12 deficiency [3,19] c) folate supplementation can improve (or mask) the anemia of vitamin B12 deficiency, but will not prevent or improve the neuropathology 2) parenteral vitamin B12 may be required in special circumstances a) indications - intrinsic factor deficiency & failure of ileal absorption - severe anemia - neurologic dysfunction - failure to respond to oral therapy - malabsorption syndromes b) dosage - 1 mg IM weekly for 1 month (former recommendation) [3] - 1 mg IM monthly until absorption malfunction corrected [3] 3) consider endoscopy: - increased risk of gastric cancer & gastric carcinoid 4) prognosis a) behavioral symptoms & peripheral neuropathy respond within 6 months of treatment, but often fail to completely remit b) it is rare for the dementia to reverse c) hematologic values normalize in 2 months d) no evidence that finding a cause for B12 deficiency improves outcomes [20]; - treat emipirically with cyanocobalamin 1 mg sublingual QD

Interactions

disease interactions

Related

intrinsic factor; gastric intrinsic factor; IF; INF (GIF, IFMH) megaloblastic anemia methylmalonate in serum pernicious anemia; autoimmune gastritis Schilling test subacute combined degeneration of spinal cord; Lichtheim's disease; Putnam-Dana Syndrome vitamin B12 in serum/plasma vitamin B12; cobalamin

Specific

transcobalamin II deficiency

General

vitamin B deficiency gastrointestinal disease

Database Correlations

OMIM 250940

References

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  17. Prescriber's Letter 12(7): 2005 Oral Vitamin B12 in the Treatment of Vitamin B12 Deficiency Detail-Document#: 210713 (subscription needed) http://www.prescribersletter.com
  18. Prescriber's Letter 16(8): 2009 Metformin-Induced Vitamin B12 Deficiency: Can it Lead to Peripheral Neuropathy? Detail-Document#: 250803 (subscription needed) http://www.prescribersletter.com
  19. Prescriber's Letter 18(8): 2011 Treatment of Vitamin B12 Deficiency Detail-Document#: 270811 (subscription needed) http://www.prescribersletter.com
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  31. DeFilippis EM, Petersen A, Yialamas MA Progressive Weakness and Memory Impairment in a Middle-aged Man. JAMA. 2018;320(2):197-198. July 10 PMID: 29998320 https://jamanetwork.com/journals/jama/fullarticle/2687336
  32. Khardori R Fast Five Quiz: Vitamin B12 Deficiency Medscape. December 22, 2020 https://reference.medscape.com/viewarticle/942750
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  34. Pluvinage JV, Ngo T, Fouassier C et al Transcobalamin receptor antibodies in autoimmune vitamin B12 central deficiency. Sci Transl Med. 2024 Jun 26;16(753):eadl3758 PMID: 38924428 https://www.science.org/doi/10.1126/scitranslmed.adl3758