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Argomenti di Ematologia: le anemie non sideropeniche La anemia megaloblastica Dipartimento di Scienze Biomediche – Sezione di Ematologia Università degli.

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Presentation on theme: "Argomenti di Ematologia: le anemie non sideropeniche La anemia megaloblastica Dipartimento di Scienze Biomediche – Sezione di Ematologia Università degli."— Presentation transcript:

1 Argomenti di Ematologia: le anemie non sideropeniche La anemia megaloblastica Dipartimento di Scienze Biomediche – Sezione di Ematologia Università degli Studi di Catania

2 Megaloblastic/Macrocytic Anemia Cobalamin (vitamin B12) Deficiency Folate Deficiency

3 cobalamingastric intrinsic factor (IF) Terminal ileum cobalamin Small bowel Meat Fish Milk Cheese 3-9 µg/day Needs ≤ 2µg/day Liver store (5mg) Serum B12 levels pg/ml Cobalamin (vitamin B12) Toh B-H et al, N Engl Med 1997 Babior BM, Hamson’s Principles of Int Med, 2001 DNA and methyonine synthesis Methyl B12 methylmalonate to succynil Deossi B12

4 Folate Fruits and vegetables µg/day Low liver store (5-10 mg) (2-4 months) Amino acid and nucleic acid metabolism Serum folate ng/ml (folate intake-dependent) Red-cell folate ng/ml (cobalamin levels-dependent) Pawson R et al, Aliment Pharmacol Ther 1998 Gregory JF et al, Annu Rev Nutr 2002 Duodenum Jejunum Methionina synthesis (Conjugase) (ratio 1/30)

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6 Low intake (rare) Malabsorption related to the lack of intrinsic factor Consumption Infections (botriocephalus) autoimmune gastritis (genetic predisposition) gastrectomy Toh B-H et al, N Engl Med 1997 Half danarson TR et al, Blood 2007 B12 deficiency Alcohol Drugs (antisecretories) Pancreatitis Malabsorption related to terminal ileum tropic sprue chron celiac disease resection (blind gut syndrome) limphoma irradiation genetic conditions (IF or transcobalamin I/II deficiency)

7 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) ethilism toxicomania elderly Increased needs Increased loss dialysis Halfdanarson TR et al, Blood 2007 pregnancy chronic hemolytic anemia, leukemias, chron, rheumatoid arthritis dermatitis Malabsorption tropic sprue celiac disease

8 Megaloblastic Anemia: “pernicious” Stomach fundus and body Autoimmune chronic gastritis Parietal cell H+/K+-ATPase autoantibodies Acid- and IF secreting parietal cells and pepsinogen- secreting zymogenic cells gastric juice autoantibodies to vit B12-binding site of IF Type A gastritis Antrum spared Antibodies to parietal cells and IF Low serum pepsinogen I levels Achlorhydria Hypergastrinemia B12-deficient megaloblastosis Submucosal and lamina propria infiltration (Plasmacells, macrophages and CD4 T cells) Toh B-H et al, N Engl J Med 1997 Fyfe JC et al, Blood 2004

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12 Protean H pylori: perhaps “pernicious” too? Bacterial chronic gastritis Stomach antrum Gastrin-producing cells H pylori infection Type B gastritis Antrum involved H pylori infection Hypogastrinemia Type A gastritis H pylori camouflag e (H+K+-ATPase) Hershko C et al, Blood 2006 years or decades

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14 Clinical Presentation Anemia Fatigue Gastrointestinal Manifestation Atrophic glossitis Diarrhea Malabsorption Weight loss 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 manifestatio Cerebral manifestation (mild personality defects, memory loss, frank psychosis “megaloblastic madness”) Cancer complications (gastric carcinoma and gastric carcinoid tumors due to trophic action of hypergastrinemia, 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 smea Peripheral-Blood smear Macrocytosis with hypersegmented polymorphonuclear leukocytes Blood marrow smear (ineffective myelopoiesis) Megaloblasts and large myeloid precursors (“giant metamyelocytes”) Folate - Laboratory Low serum and red cell folate Elevated serum homocysteine and normal serum methylmalonic acid It is recommended combined mesurements of both vitamins Toh B-H et al, N Engl J Med 1997 Halfdanarson TR et al, Blood 2007 B12 - Laboratory Low serum vit B12, normal or high serum folate and low red cell folate Elevated serum homocysteine and methylmalonic acid Schilling’test Low serum holotranscobalamin II (holoTC saturation) Bone marrow biopsy (MDS) Normal B12, folate and homocysteine and hyposegmented polymorphonuclear Peripheral blood Anemia (normocromic/macrocytic) Leukopenia Thrombocytopenia Pancytopenia FIGLU test Elevated urinary formiminoglutammic acid

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17 Old and New vit B12 absorption test Traditional Shilling’s test Labeled B12 Used to investigate whether lack of the vitamin is caused by lack of IF Urinary excretion of orally administered labeled B12 without IF Holo-TC Absorption test Non labeled B12 Used to investigate whether lack of the vitamin is caused by lack of IF vitamin is caused by lack of IF Measurement of holoTC before and 24 hours after intake of B12 without rhIF and again 24 hours after intake of B12 together with rhIF (rhIF-B12) B12 together with rhIF (rhIF-B12) Hvas AM et al, Haematologica 2006 Low Labeled B12 with IF Normal free B12 rhIF-B12 mild holoTC increase high holoTC increase

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20 Laboratory Diagnosis - Serologic and bioptic Studies B12 Serum and juice autoantibodies to gastric parietal cells Serum 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 hyperbilirubin Gastric biopsy Toh B-H et al, N Engl J Med 1997

21 TREATMENT Regular daily intramuscolar injections of 100 μg of vit B12 for two weeks. Regular weekly intramuscolar injections of 100 µg of vit. B12 until normalization of hemoglobin. Indefinite monthly intramuscolar injections of 100 µg of vit. B12 in patients with chronic disease. Tablets of 25 μg to 1 mg of vit B12 daily to prevent the deficiency in elderly patients with gastric atrophy Regular daily oral of 1-5 mg of folate for two years. Vidal-Alaball J et al, Cochrane Database Syst Rev 2005 Halfdanarson TR vet al, Blood 2007


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