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