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Argomenti di Ematologia: le anemie non sideropeniche
La anemia megaloblastica
Dipartimento di Scienze Biomediche – Sezione di EmatologiaUniversità degli Studi di Catania
Megaloblastic/Macrocytic Anemia
Cobalamin(vitamin B12)
Deficiency
FolateDeficiency
cobalamin gastric intrinsic factor(IF)
Terminal ileum
cobalaminSmallbowel
MeatFishMilkCheese
3-9 µg/dayNeeds ≤ 2µg/day
Liver store(5mg)
Serum B12 levels 193-982 pg/ml
Cobalamin (vitamin B12)
Toh B-H et al, N Engl Med 1997Toh B-H et al, N Engl Med 1997Babior BM, Hamson’s Principles of Int Med, 2001Babior BM, Hamson’s Principles of Int Med, 2001
DNA and methyonine synthesisMethyl B12
methylmalonateto
succynil
Deossi B12
Folate
Fruitsand vegetables
100-200 µg/day
Low liver store(5-10 mg)(2-4 months)
Amino acid and nucleic acid metabolism
Serum folate 3.0-17.0 ng/ml (folate intake-dependent)Red-cell folate 225-640 ng/ml (cobalamin levels-dependent)
Pawson R et al, Aliment Pharmacol Ther 1998Pawson R et al, Aliment Pharmacol Ther 1998Gregory JF et al, Annu Rev Nutr 2002Gregory JF et al, Annu Rev Nutr 2002
DuodenumJejunum
Methionina synthesis
(Conjugase)
(ratio 1/30)
Low intake (rare)
Malabsorption related to the lack of intrinsic factor
ConsumptionInfections (botriocephalus)
autoimmune gastritis (genetic predisposition)gastrectomy
Toh B-H et al, N Engl Med 1997Toh B-H et al, N Engl Med 1997Half danarson TR et al, Blood 2007Half danarson TR et al, Blood 2007
B12 deficiency
Alcohol
Drugs (antisecretories)
Pancreatitis
Malabsorption related to terminal ileumtropic spruechronceliac diseaseresection (blind gut syndrome)limphomairradiationgenetic conditions (IF or transcobalamin I/II deficiency)
Folate Deficiency
Low intake
Drugs (diidrofolate reductase inhibitors, intestinal”conjugase”)antifolates (metotrexate, pirimetamine, thrimetoprim, sulfasalazine)purine analogs (mercaptopurine, thioguanine, azathioprine, aciclovir)pirimidine analogs (fluorouracile, zidovudine)RNA reductase inhibitors (hydroyurea, cytarabine)anticonvulsive (difenilidantoine, phenobarbital)Others (anaesthetic, contraceptives)
ethilismtoxicomania
elderly
Increased needs
Increased lossdialysis Halfdanarson TR et al, Blood 2007Halfdanarson TR et al, Blood 2007
pregnancychronic hemolytic anemia, leukemias, chron, rheumatoid arthritisdermatitis
Malabsorptiontropic sprueceliac disease
Megaloblastic Anemia: “pernicious”
Stomachfundus
andbody
Autoimmunechronic gastritis
Parietal cellH+/K+-ATPaseautoantibodies
Acid- and
IF secretingparietal cells and
pepsinogen-secreting zymogenic cells
gastric juiceautoantibodies
to vit B12-binding site of IF
Type A gastritis
Antrum sparedAntibodies to parietal cells and IFLow serum pepsinogen I levelsAchlorhydriaHypergastrinemiaB12-deficient megaloblastosisSubmucosal and lamina propria infiltration(Plasmacells, macrophages and CD4 T cells)
Toh B-H et al, N Engl J Med 1997Toh B-H et al, N Engl J Med 1997Fyfe JC et al, Blood 2004Fyfe JC et al, Blood 2004
Protean H pylori: perhaps “pernicious” too?
Bacterial chronic gastritis
Stomach antrum Gastrin-producing cells
H pyloriinfection
Type B gastritis
Antrum involvedH pylori infectionHypogastrinemia
Type A gastritis
H pylori camouflage(H+K+-ATPase)
Hershko C et al, Blood 2006Hershko C et al, Blood 2006
yearsor
decades
Clinical PresentationClinical Presentation
AnemiaAnemiaFatigue
Gastrointestinal ManifestationGastrointestinal ManifestationAtrophic glossitis
DiarrheaMalabsorption
Weight loss
Neurologic Complications (acid methylmalonic)Neurologic 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 manifestatioCerebral manifestation(mild personality defects, memory loss, frank psychosis “megaloblastic madness”)
Cancer complicationsCancer 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 1997Toh B-H et al, N Engl J Med 1997
Laboratory Diagnosis – Hematologic studiesLaboratory Diagnosis – Hematologic studiesPeripheral-Blood smeaPeripheral-Blood smearMacrocytosis with hypersegmented polymorphonuclear leukocytes
Blood marrow smear (ineffective myelopoiesis)Blood marrow smear (ineffective myelopoiesis)Megaloblasts and large myeloid precursors (“giant metamyelocytes”)
Folate - LaboratoryFolate - LaboratoryLow serum and red cell folateLow serum and red cell folate
Elevated serum homocysteine and normal serum methylmalonic acidElevated serum homocysteine and normal serum methylmalonic acid
It is recommended combined mesurements of both vitaminsIt is recommended combined mesurements of both vitamins Toh B-H et al, N Engl J Med 1997Toh B-H et al, N Engl J Med 1997Halfdanarson TR et al, Blood 2007Halfdanarson TR et al, Blood 2007
B12 - 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)
Bone marrow biopsy (MDS)Normal B12, folate and homocysteine and hyposegmented polymorphonuclear
Peripheral bloodAnemia (normocromic/macrocytic)LeukopeniaThrombocytopeniaPancytopenia
FIGLU testElevated urinary formiminoglutammic acid
Old and New vit B12 absorption test
Traditional Shilling’s testLabeled B12
Used to investigate whether lack of the vitamin is caused by lack of IF
Urinary excretion of orallyUrinary excretion of orallyadministered labeled B12 without IFadministered labeled B12 without IF
Holo-TC Absorption testHolo-TC Absorption testNon labeled B12Non labeled B12
Used to investigate whether lack of theUsed to investigate whether lack of the vitamin is caused by lack of IFvitamin is caused by lack of IF
Measurement of holoTC before andMeasurement of holoTC before and24 hours after intake of B12 without 24 hours after intake of B12 without rhIF and again 24 hours after intake ofrhIF and again 24 hours after intake of B12 together with rhIF (rhIF-B12)B12 together with rhIF (rhIF-B12)
Hvas AM et al, Haematologica 2006Hvas AM et al, Haematologica 2006
Low
Labeled B12 with IF
Normal
free B12 rhIF-B12
mild holoTC increase high holoTC increase
Laboratory Diagnosis - Serologic and bioptic StudiesLaboratory Diagnosis - Serologic and bioptic StudiesB12B12
Serum and juice autoantibodies to gastric parietal cellsSerum and juice autoantibodies to gastric parietal cellsSerum and juice autoantibodies to IF type I Serum and juice autoantibodies to IF type I (block the binding vit B12/IF “70%”)(block the binding vit B12/IF “70%”)Serum and juice autoantibodies to IF type II Serum and juice autoantibodies to IF type II (block vit B12/IF complex “35-40%”)(block vit B12/IF complex “35-40%”)
Mild indirect hyperbilirubin Mild indirect hyperbilirubin
Gastric biopsyGastric biopsy
Toh B-H et al, N Engl J Med 1997Toh B-H et al, N Engl J Med 1997
TREATMENTTREATMENT
Regular daily intramuscolar injections of 100 Regular daily intramuscolar injections of 100 μμg of vit B12 g of vit B12 for two weeks.for two weeks.Regular weekly intramuscolar injections of 100 Regular weekly intramuscolar injections of 100 µg of vit. B12 µg of vit. B12 until normalization of hemoglobin.until normalization of hemoglobin.Indefinite monthly Indefinite monthly intramuscolar injections of 100 intramuscolar injections of 100 µg of vit. B12 µg of vit. B12 in patients with chronic disease.in patients with chronic disease.
Tablets of 25 Tablets of 25 μμg to 1 mg of vit B12 daily to prevent the deficiency g to 1 mg of vit B12 daily to prevent the deficiency in elderly patients with gastric atrophyin elderly patients with gastric atrophy
Regular daily oral of 1-5 mg of folate for two years.Regular daily oral of 1-5 mg of folate for two years.
Vidal-Alaball J et al, Cochrane Database Syst Rev 2005Vidal-Alaball J et al, Cochrane Database Syst Rev 2005Halfdanarson TR vet al, Blood 2007Halfdanarson TR vet al, Blood 2007