6 Infections (botriocephalus) B12 deficiencyLow intake (rare)AlcoholDrugs (antisecretories)Malabsorption related to the lack of intrinsic factorautoimmune gastritis (genetic predisposition)gastrectomyMalabsorption related to terminal ileumtropic spruechronceliac diseaseresection (blind gut syndrome)limphomairradiationgenetic conditions (IF or transcobalamin I/II deficiency)ConsumptionInfections (botriocephalus)Toh B-H et al, N Engl Med 1997Half danarson TR et al, Blood 2007Pancreatitis
8 secreting zymogenic cells Megaloblastic Anemia: “pernicious”AutoimmunechronicgastritisParietal cellH+/K+-ATPaseautoantibodiesType A gastritisAntrum sparedAntibodies to parietal cells and IFLow serum pepsinogen I levelsAchlorhydriaHypergastrinemiaB12-deficient megaloblastosisSubmucosal and lamina propria infiltration(Plasmacells, macrophages and CD4 T cells)gastric juiceautoantibodiesto vit B12-bindingsite of IFAcid-andIF secretingparietal cells andpepsinogen-secreting zymogenic cellsStomachfundusandbodyToh B-H et al, N Engl J Med 1997Fyfe JC et al, Blood 2004
14 Clinical Presentation AnemiaFatigueGastrointestinal ManifestationAtrophic glossitisMalabsorptionDiarrheaWeight lossNeurologic Complications (acid methylmalonic)Peripheral neuropathy (paresthesias, numbness)Spinal cord posterior column(loss of vibration and position sense, and sensory ataxia with positive Romberg)Spinal cord lateral column(limb weakness, spasticity, and extensor plantar responses)Cerebral manifestation(mild personality defects, memory loss, frank psychosis “megaloblastic madness”)Cancer complications(gastric carcinoma and gastric carcinoid tumors due to trophic action ofhypergastrinemia, colon and uterus tumor due to megaloblastic metaplasia)Toh B-H et al, N Engl J Med 1997
15 Laboratory Diagnosis – Hematologic studies Peripheral-Blood smearMacrocytosis with hypersegmented polymorphonuclear leukocytesPeripheral bloodAnemia (normocromic/macrocytic)LeukopeniaThrombocytopeniaPancytopeniaBlood marrow smear (ineffective myelopoiesis)Megaloblasts and large myeloid precursors (“giant metamyelocytes”)Bone marrow biopsy (MDS)Normal B12, folate and homocysteine and hyposegmented polymorphonuclearB12 - LaboratoryLow serum vit B12, normal or high serum folate and low red cell folateElevated serum homocysteine and methylmalonic acidSchilling’testLow serum holotranscobalamin II (holoTC saturation)Folate - LaboratoryLow serum and red cell folateElevated serum homocysteine and normal serum methylmalonic acidFIGLU testElevated urinary formiminoglutammic acidToh B-H et al, N Engl J Med 1997Halfdanarson TR et al, Blood 2007It is recommended combined mesurements of both vitamins
17 Traditional Shilling’s test Holo-TC Absorption test Old and New vit B12 absorption testTraditional Shilling’s testLabeled B12Holo-TC Absorption testNon labeled B12Used to investigate whether lack of thevitamin is caused by lack of IFUsed to investigate whetherlack of the vitamin iscaused by lack of IFMeasurement of holoTC before and24 hours after intake of B12 withoutrhIF and again 24 hours after intake ofB12 together with rhIF (rhIF-B12)Urinary excretion of orallyadministered labeled B12 without IFLowfree B12rhIF-B12Labeled B12 with IFmild holoTC increasehigh holoTC increaseNormalHvas AM et al, Haematologica 2006
20 Laboratory Diagnosis - Serologic and bioptic Studies Serum and juice autoantibodies to gastric parietal cellsSerum and juice autoantibodies to IF type I(block the binding vit B12/IF “70%”)Serum and juice autoantibodies to IF type II(block vit B12/IF complex “35-40%”)Mild indirect hyperbilirubinGastric biopsyToh B-H et al, N Engl J Med 1997
21 Regular daily intramuscolar injections of 100 μg of vit B12 TREATMENTRegular daily intramuscolar injections of 100 μg of vit B12for two weeks.Regular weekly intramuscolar injections of 100 µg of vit. B12until normalization of hemoglobin.Indefinite monthly intramuscolar injections of 100 µg of vit. B12in patients with chronic disease.Tablets of 25 μg to 1 mg of vit B12 daily to prevent the deficiencyin elderly patients with gastric atrophyRegular daily oral of 1-5 mg of folate for two years.Vidal-Alaball J et al, Cochrane Database Syst Rev 2005Halfdanarson TR vet al, Blood 2007
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